This invention relates to methods of preparing pressure sensitive adhesive matrix patch devices for transdermal drug delivery. More particularly, the invention relates to the preparation of pressure sensitive adhesive matrix patches by dissolving hydrophilic salts of hydrophobic drugs that are crystalline at room temperature in aqueous dispersions of hydrophobic pressure sensitive adhesive polymers. These patches are surprisingly free from drug crystals upon drying and exhibit unusually good physical stability without the use of a solubilizing agent or crystal growth inhibitor.
Transdermal delivery of various drugs and pressure sensitive adhesive matrix patches for transdermal delivery of such drugs are well known in the art of drug delivery. These matrix patches include a pressure sensitive adhesive layer for affixing the patch to the skin and for carrying the drug and any excipients that are directly incorporated into this adhesive layer. These adhesive matrix patches also typically include an inert, impervious backing layer and a release liner that is peeled off and discarded before applying the patch to the skin. These patches are distinguished from reservoir patches in that the drug in a reservoir patch is incorporated in a layer or compartment separate from the pressure sensitive adhesive layer. An example of a reservoir transdermal patch is described in U.S. Pat. No. 5,120,546 to Hansen et al.
The polymers used to form pressure sensitive adhesives are well known to those skilled in the art and will be discussed in greater detail below. Since these polymers are hydrophobic in nature, they are typically supplied in liquid form, either dissolved in organic solvents (solvent-based adhesives) or as two-phase aqueous dispersions of water-insoluble polymer particles (water-based adhesives). I. Benedek and J. L. Heymans, Pressure-Sensitive Adhesives Technology 34 (1997).
Drugs or pharmaceutical agents that are incorporated into pressure sensitive adhesive matrix patches are often available as either hydrophobic water-insoluble free drugs or as hydrophilic water-soluble salts. These hydrophilic drug salt derivatives are well known in the art and are often the forms that are developed for oral delivery.
In some patents it is suggested that the hydrophobic free drug form of a drug and the hydrophilic salt form of a drug may be freely substituted in a transdermal pressure sensitive adhesive matrix patch. For example, U.S. Pat. No. 5,149,538 to Granger discloses a pressure sensitive adhesive matrix incorporating opioids or their pharmaceutically acceptable salts, however, no mention is made of the means of manufacture or the specific types of adhesives that might be compatible with such opioid drugs or drug salts. Free form drugs and their corresponding salts will normally differ in their physico-chemical properties such as solubility and hydrophobicity. Therefore, it is unlikely that the free drug and salt forms can be freely substituted in a given adhesive. The free drug form is likely to be insoluble in the water phase of an aqueous emulsion pressure sensitive adhesive, while the hydrophilic salt form is likely to be insoluble in the organic solvents of a solvent-based pressure sensitive adhesive.
It is well known in the art that a transdermal delivery system suitable for one drug or drug form may not be suitable for use with another drug or drug form. For example, U.S. Pat. No. 5,633,009 to Kenealy et al. suggests that azapirones and azapirone salts may be freely interchanged in pressure sensitive matrix patches, but discloses only techniques for incorporating hydrophobic azapirone free base in a solvent-based hydrophobic polyisobutylene adhesive. U.S. Pat. No. 5,589,498 to Mohr et al. suggests that ketorolac and ketorolac salts may be freely substituted in transdermal matrix devices, but only discloses techniques for incorporating hydrophobic ketorolac free acid in a hydrophobic solvent-based pressure sensitive acrylic adhesive and techniques for incorporating hydrophilic ketorolac tromethamine in hydrophilic polymers (hydrogels, polyurethane, or pectin/gelatin blends). These examples serve to illustrate that hydrophilic salt forms of drugs are known in the art to be compatible with water-soluble hydrophilic polymers and hydrophobic drug forms are known to be compatible with solvent-based hydrophobic polymers such as are used in typical pressure sensitive adhesives.
For manufacturing transdernal pressure sensitive matrix patches using hydrophilic drug salts, the hydrophilic salt is commonly converted to the hydrophobic free base This conversion and subsequent incorporation in a solvent-based hydrophobic pressure sensitive adhesive polymer is well known in the art. U.S. Pat. No. 5,002,773 to Keshary et al. describes transdermal delivery of a calcium antagonist compound, xe2x80x9cTA-3090.xe2x80x9d Keshary states that the free base form of TA-3090 can be incorporated in polymeric matrix materials in a higher concentration than the maleate salt of TA-3090 and that the free base form is preferred for transdermal delivery. U.S. Pat. No. 4,201,211 to Chandrasekaran et al. discloses a gelled mineral oil-polyisobutylene skin patch for transdermal delivery that incorporates clonidine free base. Oral clonidine tablets, however, are manufactured with the clonidine hydrochloride salt. U.S. Pat. No. 4,262,003 to Urquhart et al. describes a gelled mineral oil-polyisobutylene-scopolamine free base transdermal patch for the administration of scopolamine base. U.S. Pat. No. 4,956,171 to Chang provides examples of the conversion of buprenorphine salts into buprenorphine free base for incorporation into an organic solvent-based pressures sensitive adhesive. These examples serve to illustrate the conversion of a hydrophilic salt form of a drug into the more hydrophobic free base form to render it compatible for incorporation into a hydrophobic pressure sensitive adhesive matrix patch.
Water-based hydrophobic pressure sensitive adhesives are also known in the art. These are two-phase systems wherein the hydrophobic pressure sensitive adhesive polymer is dispersed as particles in water. U.S. Pat. No. 4,564,010 to Coughlan et al. discloses a water-based pressure sensitive adhesive emulsion film for medical use comprising a base layer laminated to a water-based pressure sensitive adhesive coating formed of a mixture of a polyacrylic latex, an ester resin, and a thickening agent. Coughlan teaches that such films can be used in transdermal delivery systems as peripheral adhesives, with the drug being incorporated in a separate element. The possibility of incorporating the drug and optional permeation enhancers into the water-based pressure sensitive layer is not considered. U.S. Pat. No. 4,409,206 to Stricker et al. discloses a means of manufacturing a patch for transdermal drug delivery using acrylic polymer dispersions. In this invention the acrylic dispersion is dried and the hydrophobic drug substances are then allowed to diff-use into the dried film from drug solutions or suspensions in organic solvents, which are subsequently evaporated. The mixing of a water soluble drug salt in an aqueous dispersion and preparing a polymer matrix film in a single coating and drying step was not recognized or discussed.
The manufacture of transdermal matrix patch devices that use water-based pressure sensitive adhesive dispersions has been contemplated in the art, but the incorporation of hydrophilic salts of crystalline drugs in such dispersions has not been considered. U.S. Pat. No. 5,230,896 to Yeh et al. discloses a transdermal delivery system for administration of nicotine comprising nicotine base, an acrylic polymer adhesive, a stabilizer, and a polyester film backing. It is stated that a nicotine salt is also contemplated in the practice of the invention. Such a nicotine salt is used to reduce volatility of the drug and is formed in situ by addition of acid. Nicotine is an unusual compound in that the free base is quite hydrophilic and is a liquid at room temperature. Both nicotine free base and its salts are very water soluble. U.S. Pat. No. 5,186,938 to Sablotsky et al. describes the use of a water-based emulsion adhesive patch for the transdermal administration of nitroglycerin. Nitroglycerin is not an ionizable salt and is liquid at room temperature with appreciable water solubility.
An important consideration for transdermal delivery of drugs or drug salts that are crystalline at room temperature is ensuring that the drug is dissolved in the pressure sensitive adhesive and does not recrystallize over time once it has been incorporated in the dried adhesive film. If the drug is not physically stable and recrystallization occurs during the shelf-life of the transdermal system, inconsistent in vitro drug release and variable in vivo drug delivery could result, thus making the transdermal system unacceptable for use. Techniques known in the art for preventing the recrystallization of drug substances include the incorporation of solubilizing agents to increase the equilibrium solubility of the drug or addition of crystal growth inhibitors to slow the rate of crystal formation. Examples of these approaches can be found in U.S. Pat. No. 5,336,210 to Hidaka et al., which discloses a physically stabilized estradiol pressure sensitive matrix, and U.S. Pat. No. 5,633,009 to Kenealy et al., which discloses an pressure sensitive adhesive matrix patch for azapirones containing isocetyl alcohol as a solubilizer.
In view of the foregoing, it will be appreciated that providing a method of manufacturing physically stable hydrophobic pressure sensitive adhesive matrix patches for transdermal delivery using hydrophilic crystalline drug salts would be a significant advancement in the art.
It is an object of the present invention to provide a method of making a physically stable pressure sensitive adhesive matrix patch for transdermal drug delivery using a hydrophilic salt of a hydrophobic drug and an aqueous dispersion of hydrophobic pressure sensitive adhesive polymers.
It is another object of the invention to provide a method of making a pressure sensitive adhesive matrix patch using a hydrophilic salt of a hydrophobic drug wherein the drug is rendered physically stable.
It is also an object of the invention to provide a method of increasing transdermal flux of a drug wherein the drug delivery patch is made with a hydrophilic salt of the drug.
These and other objects can be addressed by providing a method of preparing a pressure sensitive adhesive matrix patch device comprising the steps of:
(a) dissolving an effective amount of a hydrophilic salt form of a drug with an aqueous dispersion, comprising a water phase, of a hydrophobic pressure sensitive adhesive and optionally a permeation enhancer, to form a mixture;
(b) film casting the mixture and evaporating the water phase to obtain a hydrophobic pressure sensitive adhesive matrix film having the drug fully dissolved therein and having first and second surfaces thereof; and
(c) laminating a release liner to the first surface of the matrix film and a substantially drug-impermeable backing layer to the second surface.
Preferably, the water-based adhesive is an acrylic copolymer, ethylene-vinyl acetate copolymer, or polyisobutylene polymer or copolymer that is a two-phase dispersion of water-insoluble polymer particles in water.
Illustrative drugs that can be incorporated into such patches by this method include albuterol sulfate, ketorolac tromethamine, diclofenac sodium, buspirone HCl, lidocaine HCl, clonidine HCl, and warfarin sodium. The matrix film can further comprise an effective amount is of a permeation enhancer selected from the group consisting of cell envelope disordering compounds, solvents, and mixtures thereof.
A method of inhibiting crystallization of a drug in a pressure sensitive adhesive matrix patch comprises:
(a) dissolving an effective amount of a hydrophilic salt form of the drug with an aqueous dispersion, comprising a water phase, of a hydrophobic pressure sensitive adhesive to form a mixture; and
(b) film casting the mixture and evaporating the water phase to obtain a hydrophobic pressure sensitive adhesive matrix film having the drug fully dissolved therein.
A method of increasing transdermal flux of an acidic drug comprises applying a pressure sensitive adhesive matrix patch to skin, wherein the matrix patch is prepared by the steps comprising:
(a) mixing an effective amount of a hydrophilic salt form of the acidic drug with an aqueous dispersion, comprising a water phase, of a hydrophobic pressure sensitive adhesive to form a mixture;
(b) film casting the mixture and evaporating the water phase to obtain a hydrophobic pressure sensitive adhesive matrix film having the acidic drug fully dissolved therein and having first and second surfaces thereof; and
(c) laminating a release liner to the first surface of the matrix film and a substantially drug-impermeable backing layer to the second surface.
A method of preparing a drug/adhesive layer of a pressure sensitive adhesive matrix patch device comprises the steps of:
(a) dissolving an effective amount of a hydrophilic salt form of the drug with an aqueous dispersion, comprising a water phase, of a hydrophobic pressure sensitive adhesive to form a mixture; and
(b) film casting the mixture and evaporating the water phase to obtain a hydrophobic pressure sensitive adhesive matrix film having the drug fully dissolved therein.
A method of inhibiting crystallization of a drug in a drug/adhesive layer of a pressure sensitive adhesive matrix patch comprises the steps of:
(a) dissolving an effective amount of a hydrophilic salt form of the drug with an aqueous dispersion, comprising a water phase, of a hydrophobic pressure sensitive adhesive to form a mixture; and
(b) film casting the mixture and evaporating the water phase to obtain a hydrophobic pressure sensitive adhesive matrix film having the drug fully dissolved therein.